Antihypertensive (hypotensive drugs)

Antihypertensive 

(hypotensive drugs)

Antihypertensives

Antihypertensives reduce high blood pressure. 
Arterial hypertension (AH) – a syndrome that accompanies many diseases. 

• primary hypertension (essential hypertension);
• secondary (symptomatic) hypertension.

Arterial hypertension (AH)

For instance, hypertension accompanying  renal disease: 

• Renoparenchymal hypertension (glomerulonephritis, pyelonephritis);
• Renovascular hypertension (in case of renal artery constriction). 

Hypertension during pheochromocytoma (tumor of the adrenal medulla), hyperaldosteronism (adrenal cortex), etc.

• At the initial stage of the disease, hypertension  is associated with an increased tone of the sympathetic nervous system, which leads to the increase in cardiac output and constriction of blood vessels. At this stage, the most effective are the drugs that reduce the blood pressure by decreasing the influence of the sympathetic nervous system (antihypertensive drugs of central action, adrenblockers).
  
• At the later stages of essential hypertension, and in case of renal disease, high blood pressure is associated with the activation of the renin – angiotensin system.

The formed angiotensin II

exerts a direct vasoconstricting effect;

• stimulates the sympathetic nervous system (increases the stimulating effect of the sympathetic nervous system on the heart and blood vessels);
• increases the aldosterone secretion by the adrenal cortex. 

Aldosterone stimulates the reabsorption of  Na + and water in the renal tubules, resulting in the constriction of the blood vessels and increase of the volume of blood plasma. 
At this stage the most effective drugs are the ones reducing the formation of renin (β-adrenoblockers), preventing from the formation of angiotensin II (inhibitors of angiotensin-converting enzyme – ACE), blocking the angiotensin II receptors in tissues (blockers of  angiotensin АТ1-receptors).
One of the reasons of AH is an increased volume of circulating blood, often associated with an excessive use of NaCl (sodium-volume dependent AH). 
At the young age excess of Na + is excreted by natriuretic peptides, in  particular by the atrial natriuretic peptide.  
With age, their production decreases and then an excess of NaCl leads to hypertension. 
High level of Na + in the smooth muscles of blood vessels leads to their constriction. 
As a result, the blood pressure increases. 
At the sodium-volume dependent AH diuretics are effective, which remove excess of Na + from the body. 
During hypertension of any origin antihypertensives of myotropic action are effective.

Classification of antihypertensive drugs

1. Drugs reducing the influence of the sympathetic nervous system (neurotropic antihypertensives)
A. Drugs of central action;
B. Drugs blocking sympathetic innervation;
2. Myotropic antihypertensives:
A. NO donators;
B. activators of potassium channels;
C. calcium channel blockers;
D. other myotropic antihypertensives;
3. Drugs reducing the influence of the renin-angiotensin system:
A. Drugs inhibiting the formation of angiotensin II (drugs that reduce the secretion of rennin, ACE inhibitors, vasopeptidase inhibitors);
B. AT1-receptor blockers.
4. Diuretics.

Drugs reducing the influence of the sympathetic nervous system (neurotropic antihypertensives)

The highest centers of the sympathetic nervous system are located in the hypothalamus. From here the excitation is transmitted to the vasomotor center of the sympathetic nervous system, located in the rostro-ventrolateral region. From this center impulses are transmitted to the sympathetic centers in the lateral horn of the spinal cord and then along the  sympathetic innervation to the heart and blood vessels. Activation of vasomotor center increases the frequency and strength of heart contractions (increase in cardiac output) and raised tone of blood vessels – high blood pressure.   
The reduction of  blood pressure is possible due to the inhibition of centers of the sympathetic nervous system and due to the block the sympathetic innervation. Thus, neurotropic antihypertensives are divided into the drugs of central and peripheral action.

Drugs of central action

Clonidine, moxonidine, rilmenidine, guanfacine, methyldopa
Clonidine (Clophelin, Haemiton)
Pharmacodynamics. Partial agonist with high affinity to α2-adrenoceptors located in the baroreceptor center of medulla oblongata. At the same time inhibitory neurons are stimulated that depress the vasomotor center and centers of n.vagus. 
Clonidine stimulates imidazoline I1-receptors. 
This reduces the concentration of noradrenaline in plasma, reduces the stimulating effect of the sympathetic innervation of the heart and blood vessels, while the inhibiting parasympathetic influence on the heart increases. 
Cardiac output and tone of blood vessels (arterial and venous) are reduced. As a result, the blood pressure is reduced as well. 
In high doses, clonidine activates extrasynaptic α2В-adrenoreceptors, causes short-term vasoconstriction and increased blood pressure. Therefore, clonidine is administered i/v slowly – within 5-7min.
Clonidine
Pharmacokinetics. The drug is rapidly and completely absorbed in GIT; C max is observed in 1.5 hours, T1 / 2 is12-16 hours when renal function is normal, and up to 41 hours when it is disturbed. 
Excreted by kidneys in an unchanged form. The duration of action of one dose lasts for 6-24 h.    
Additional effects:
1. has a prominent sedative effect;
2. potentiates the effect of ethanol;
3. displays analgesic effects;
4.reduces opiate and alcohol abstinence.

Dosage:
The drug is effective in very small doses. Doses should be adjusted individually. When administered orally as an antihypertensive agent it is usually prescribed starting with 0.075 mg 2-4 times a day.      
In case of hypertensive crisis when taking the tablet orally does not lead to the desired effect, clonidine should be administered sublingually (tablets), i/m, s/c, or i/v. Sublingually it is used 0.15-0.3 mg. I/m or s/c – injections 0.05 - 0.15 mg (0.5 - 1.5 ml of 0.01% solution). For i/v injection 0.5-1.5 ml of 0.01% solution of clonidine is mixed in 10-20 ml of 0.9% NaCl solution and is injected slowly - for 3-5 minutes (the antihypertensive effect is seen within 3-5 minutes, reaching maximum after 15-20 minutes and lasts 4-8 hours). 
During parenteral administration and 1.5 - 2 hours after it the patient should be in the supine position (to avoid orthostatic effects).    
Parenteral administration of clonidine should be performed only in hospitals.

Adverse reactions:
1. distracted thoughts, drowsiness, depression;
2. reduced tolerance to alcohol;
3. bradycardia;
4. dry mouth and eyes;
5. nausea, constipation;
6. fluid retention;
7. impotence.

Withdrawal effect - the sudden withdrawal of the drug may lead to the blood pressure rising in 18-25hours and possible hypertensive crisis.  
Dosage forms:  tablets – 0.000075; 0.00015 and 0.0003 g (0.075, 0.15 and 0.3 mg) retard tablets – 0.0003 g (0.3 mg), 0.01% solution for injection in ampoules 1 ml (0.1 mg).

Moxonidine (Цинт)  

Pharmacodynamics. Selective cerebral stimulant of imidazoline I1- and to lesser extent α2-receptors. As a result the activity of the vasomotor center, cardiac output, and the tone of blood vessels are reduced – AP decreases. Used in different types of hypertension. Most effective in patients with mild and moderate hypertension.    
Pharmacokinetics. After ingestion it is rapidly and almost completely absorbed, bioavailability approximately 90%, Cmax - 30 - 180 minutes, T 1/2 - 2-3 hours, excreted by kidneys almost in an unchanged form.
Dosage: administered orally in doses of 0.0002 -0.0004 g (0.2 - 0.4 mg once a day, or 0.0002 g in 2 divided doses), if necessary, increase the dose to 0.0006 grams per day (in 2-3 intakes).      
Adverse reactions: dizziness, headache, dry mouth, swelling of the lower limbs, mild drowsiness.
Forms of issue: tablets 0.0002, 0.0003, 0.0004 g (0.2, 0.3, 0.4 mg).

Methyldopa (Альдомед, Dopegyt)

Pharmacodynamics. In the body it turns into α-methylnoradrenalin, and then α-methyladrenalin that stimulate α2-adrenergic receptors of vasomotor center.
Used for various forms of hypertension, including  hypertension during pregnancy. The onset of action – 4-6 hours and duration of action – 12-24 hours.
Dosage: usually administered orally in the form of tablets, for adults – starting with 0.25 (the elderly start with 0.125 g) 2-3 times a day, if necessary, increase the dose every 2 days up to 1-2 grams per day. The maximum daily dose – 3 g.
Pharmacokinetics. Taken orally, the bioavailability is 50%, C max – 2 hours, T1 / 2 – 2.8 hours. Excreted mainly by kidneys in an unchanged form. In case of renal dysfunction the drug should be administered in small doses.
Dosing regimen. Usually prescribed orally in the tablet form, adults starting with 0.25 (elderly with 0.125 g) 2-3 times a day, if necessary, the dose increase every 2 days up to 1-2 grams per day. The maximum daily dose 3 g. Keep in mind that after the termination of methyldopa the hypotensive effect ends relatively quickly – AP usually increases within 48 hours.   
Dosage forms: Tablets of 0.25 and 0.5 g. Injection – 5% solution (0.05 g in 1 ml) in ampoules or vials. Injected (instillation) 0.00025 - 0.0005 g (0.25 - 0.5 mg) in 100 ml of 5% glucose solution (for 30 - 60 minutes), if necessary, repeat injections after 6 hours.

Alpha-adrenoblockers
      Prazozin (Minipress) 

Pharmacodynamics. α - adrenergic blockers cause peripheral vasodilation by blocking the action of noradrenalin.
It has both arterial and veins dilating   action (with a little more influence on the venous vessels), that’s why it restricts the return of venous blood to the heart and makes it easier to work by reducing peripheral resistance – in other words, reduces pre- and afterload on the myocardium. 
It does not cause the decrease of minute volume of blood. Unlike usual α-blockers prazosin does not cause tachycardia but has a favorable effect on lipid blood serum parameters. 
It has a moderate cholinolytic activity. Used at various forms of hypertension. Prazosin can also be used in case of disturbances of the peripheral circulation (Raynaud's syndrome).      
Effective in the conservative treatment of prostate adenoma (prostate) at the early stage (benign prostatic hyperplasia).
Pharmacokinetics. It is rapidly absorbed in GIT, bioavailability is 50-85%, T 1/2 - 2-4h, biotransformation takes place in liver, excreted with bile in the form of metabolites.  
Dosing regimen. It should be prescribed for p/o use independently from the meal time. One starts with a small dose – 0,0005-0,001 g (0.5-1mg), which should be taken at bedtime, after which the patient must stay in bed for 6-8 hours. This is connected with the possibility of the development of "phenomenon of the first dose" – postural hypotension up to syncope (collapse).
 This reaction is even more prominent if the drug is taken after diuretics. With time prazosin  is prescribed in the following way: 0,001 g (1 mg) 2-3 times a day. The dose should be gradually increased to achieve the desired antihypertensive effect.
Dosage forms: tablets 0.0005, 0.001, 0.002 and 0.005 g (0.5, 1, 2 and 5 mg).   

Doxazosin (Artezine, Kamiren, Cardura) 

In comparison with prazosin it has a more prolonged action. Used at arterial hypertension and hypertrophy of the prostate.    
It is rapidly and almost completely absorbed, excreted mainly through the intestine in the form of metabolites.      
Prescribed orally starting with 0.001 g (1 mg) a day. Then gradually increase the dose if necessary to 0,004-0,008 grams (4.8 mg) per day. The maximum daily dose at arterial hypertension  - 0.016 (16 mg).  
Possible side effects are basically the same as the ones caused by prazosin.      
Dosage forms: tablets 0,001, 0,002; 0,004 and 0,008 g (1, 2, 4, and 8 mg).

β - blockers

one of the widely used groups of antihypertensives. At the systematic use β-blockers cause:

1. stable hypotensive effect;
2. prevent an abrupt rise in AP;
3. do not cause orthostatic hypotension;
4. have antianginal and antiarrhythmic effects.

β-blockers weaken and slow down the heart rate – systolic AP is down. 
Simultaneously, β-blockers constrict (due to blocking β2-adrenergic receptors and activation of α1-adrenergic receptors) the vessels but after 1-2 weeks of systemic use, they dilate blood vessels. 
Vasodilation is caused by restoration of baroreceptor depressor reflex, which is much weaker at AH. 
Normally, an increase in blood pressure leads to the excitation of  baroreceptors (mechanoreceptors) of carotid sinus and aortic arch, solitary tract nuclei are reflexively activated in the medulla oblongata, and by the stimulation of inhibitory cells vasomotor center is depressed. 
The stimulating influence of sympathetic innervation on heart and vessels is decreasing; cardiac output and peripheral resistance of vessels are also decreasing, AP falls.

β-adrenoblockers reduce the production of renin because of the block of  β1-adrenoreceptors of juxtoglomerular cells of kidneys. The formation of angitensin II is decreasing hence its stimulating effect on the tone of blood vessels, work of heart, aldosterone secretion is relaxed. AP falls. 
β-adrenoblockers depress presynaptic β2- adrenoreceptors of synaptic nerve fibers and decrease the noradrenalin secretion.  

 For the sytemic treatment of AH β1- adrenoblockers of long action are mostly used, such as: Atenolol, Bisoprolol (duration of action – 24 hours), Betaxolol (duration of action – 36 hours). Metoprolol decreases AP with a single dose. It is used for the symptomatic therapy of AH.

α-, β- adrenoblockers

Carvedilol (Dilatrend) reduce cardiac output (by the block of β-adrenoreceptors) and tone pf peripheral vessels (by the block of α1- adrenoreceptors). It doesn’t cause reflex tachycardia. It decreases AP after a single dose.

Myotropic antihypertensives

NO donators
These are the drugs that when metabolized release NO, identical to endothelial relaxing factor. The drugs of this group are nitroglycerine and sodium nitroprusside.  

Nitroglycerine is mainly used for CHD. As an antihypertensive drug it is administered by i/v instillations. The onset of action – 2-5 min. It is used to relieve hypertensic crisis as well as to decrease the load on heart in case of acute heart failure. 

Sodium nitroprusside – one of the most effective vasodilating and antihypertensive drugs. It dilates both arteries and veins in the dame way. Prescribed for i/v instillations. The duration of action of a single administration is around 3 minutes. It used for hypertensive crisis, acute failure of the left ventricle, for the monitored (controlled) hypotension during surgeries. 

Calcium channel blockers

They block the potential-dependent Са2+ - channels of L-type. They mainly affect the heart and arteries, but almost do not influence the veins. That’s why they do not cause orthostatic hypotension. For the long-term treatment of AH one uses: Amlodipin, Felodipin, Lacidipin, the duration of action of which is 24 hours and they are prescribed to use only once a day. Verapamil as an antihypertensive drug is indicated for the patients with coronary failure, cardiac arrhythmias. Diltiazem as an antihypertensive drug is prescribed in case of AH, vasospastic angina, supraventricular tachyarrhythmia.

ACE inhibitors

Angiotensin II – an octapeptide, formed in plasma out of the presursors under the influence of ACE – carboxypeptidase which is produced by the cells of endothelium of various organs, mainly lungs.  

By blocking the formation of angiotensin II ACE inhibitors:

• Inhibit the vasoconstricing action of angiotensin II; 
• Decrease the stimulating effect of angiotensin II on sympathetic nervous system; 
• Decrease the stimulation of synthesis and secretion of aldosterone mineralocorticoid by angiotensin. At the same time the removal of Na+ out of the body is increased while the removal of К+ is inhibited; 
• Eliminate the inactivating influence of ACE on bradykinin resulting in its higher level in blood. Bradykinin exerts a vasodilating effect, increases the penetrability of vessels, stimulates sensory nerve endings;  
• Mentioned mechanisms lead to the dilation of blood vessels and AP fall. Heart rate does not change.

Captoprilum, Lisinoprilum, Enalaprilum, Fosinoprilum, Ramiprilum, Perindoprilum

 are used for:

• AH;
• Chronic congestive heart failure;
• After myocardial infarction.

Pharmacological effects of ACE inhibitors:

• Persistent antihypertensive effect;
• Does not cause retention of sodium and water; 
• Does not cause orthostatic hypotension and reflex tachycardia; 
• No tolerance; 
• Withdrawal syndrome is not typical;  
• ACE inhibitors are effective in case of renal hypertension and at the late stages of hypertensive disease.

Captopril (Alkadil, Capoten, Blocordil etc.)

Pharmacodynamics. The drug is used for various forms of arterial hypertension including malignant, renovascular and resistant hypertension, or for hypertension in patients with insulindependent diabetes mellitus with chronic nephritis, for hypertension in newborns.
Pharmacokinetics. Taken orally, it is rapidly and almost completely absorbed (75%) in GIT. Т1/2 – about 2 hours. Biotransformation – in liver. Excretion – by kidneys in the form of metabolites in an unchanged form (up to 50%). The duration of action – 6-12 hours. 
Dosing regimen. Usually taken p/o. The initial dose for adults in case of AH is 0,0125 g (12,5 mg) 2 or 3 times a day, if necessary it is increased up to 0,025 – 0,05 g (25-50 mg)  2 or 3 times a day. In case of hypertensive crisis sublingual use is possible – 0,025-0,05 g.
Adverse reactions. Tachycardia, arrhythmia, headaches, loss of appetite, taste disturbances, skin allergic reactions, asthenia, neutropenia. Besides, in special cases proteinuria can be observed as well as nephrosis-like syndrome. While using Captopril (and other drugs of this group) an irritating dry cough is frequently noticed.  
Contraindications. Pregnancy, lactation, inclination to angioneurotic edemas, leukocytopenia and thrombocytopenia.  
Dosage forms: tablets – 0,00625; 0,0125; 0,025;0,05 0,1 g (6,25; 12,5;  25; 50 and 100 mg; capsules – 0,025 g.

Enalapril (Вазопрен, Enam, Berlipril)

Pharmacodynamics. Enalapril is a prodrug; in the body it is hydrolyzed with the formation of enaprilat which is an ACE inhibitor (Enaprilat named Enap is used in the form of   0,125% solution for the relief of hypertensive crisis). 
Indications. Various forms of AH and congestive heart failure, myocardial infarction (in complex therapy); diabetic nephropathy, secondary aldosteronism, Raynaud's disease, scleroderma.   
Pharmacokinetics. Taken orally, enalapril is rapidly absorbed but not completely (60%), bioavailibility – 40%, excretion by kidneys (up to 40% in the form of enaprilat). At the renal failure the dose should be reduced. 
Dosing regimen. Usually prescribed for p/o use (independently from the meal time). In case of AH (including renovascular one) the initial dose is 0,005 g (5 mg) once a day. With time (in1-2 weeks) the dose is adjusted individually for each patient  - usually 0,01-0,02 g (10-20 mg) once a day in 1-2 intakes. The daily dose should not exceed 0,04 g (40 mg). In any case if the AP is too low, the dose is reduced.
     Patients with hypertensive crisis get i/v administration of enaprilat – 0,00125 g (1,25 mg) which should take 5 minutes every 6 hours.
Side effects: Muscular spasms, arrhythmias, in rare cases – renal dysfunction, neutropenia. Allergic reactions are possible as well as angioneurotic edema.  
Contraindications are the same as for captopril. It shouldn’t be used in case of porphyria.
Dosage forms: tablets – 0,0025; 0,005; 0,01 and 0,02 g ( 2,5; 5; 10 and 20 mg); 0,125% solution for injections in 1 ml ampoules. 

АТ1 – receptor blockers

Angiotensin II acts through the following receptors: angiotensin1 (АТ1) and angiotensin2 (АТ2).  If АТ1-receptors of blood vessels are stimulated, phospholipase C gets activated – the level of inositoltriphosphate (IP3), that stimulates the release of Са2+ out of sarcoplasmatic reticulum, is increasing. All this leads to the constriction of blood vessels and AP rise. 
АТ1-receptor blockers: Losartan, Valsartanum, Candesartanum, Irbesartanum, Telmisartanum, Eprosartanum – prevents angiotensin II from its action onto  АТ1-receptors of vessels, sympathetic innervation and adrenal cortex. Simultaneously, the action of angiotensin II on АТ2 – receptors is increasing. It is associated with the ability of the drugs to eliminate hypertrophy of myocardium and proliferation of smooth muscles and fibroblasts of vessels.
АТ1 – receptor blockers are used for the systemic treatment of AH, chronic heart failure, especially in case of intolerance of ACE inhibitors.

Losartan

Pharmacokinetics. It is rapidly absorbed in GIT. Bioavailibility – 20-30%, Сmax – 1 hour, Т1/2 – 1,5-2 hours. Biotransformation – in liver with the formation of active metabolites. Excretion – by intestines. 
Antihypertensive effect is maintained for more than 24 hours what is conditioned by the action of Losartan metabolite which is 10-40 times more potent.    
Dosing regimen. Prescribed for p/o use. For AH it is used 0,05 g (50 mg) once a day. If necessary the dose can be increased up to 0.1 g in several weeks. The peak of an antihypertensive effect is achieved in 3-6 weeks.
Adverse reactions. Diarrhea, dizziness, headache, cough, taste disturbances, peripheral neuropathy, acute condition of angina, allergic reactions.
Contra-indications. Hyperkaliemia, pregnancy, lactation, use by children.
Dosage form. Tablets – 0,0125 and 0,05.

diuretics

Saluretics are used for the treatment of AH: Hydrochlorothiazide, Indapamidum, Chlortalidonum, Furosemidum as well as antagonists of aldosterone: Spironolactonum, Eplerenonum. Diuretics reduce high AP and do not significantly affect normal AP. If diuretics are used regularly, in the first days the volume of blood plasma is decreased what leads to the AP fall. The volume of blood plasma is gradually restored but AP doesn’t go up because of the dilated blood vessels that is associated with the removal of Na+ out of the body. If the level of Na+ is low, the exchange of extracellular Na+ for intracellular Са2+  is activated in smooth muscles of blood vessels. It leads to the relaxation of muscles and dilation of vessels. 
For antihypertensive purposes diuretics are prescribed systemically in small doses (usually once a day) for the removal of excessive amount of Na+. In such doses they effectively decrease AP without causing many side effects.  
To achieve a rapid AP fall one uses Furosemid. For systemic treatment – Hydrochlorothiazide, Chlortalidon, Indapamid.

Drugs used for the treatment of hypertensive crisis

Because of the risk of stroke in case of hypertensive crisis, the fast-acting drugs are used. If the crisis is not serious, sublingual prescription of Clonidine, Captopril is enough. Their onset of action is 15-20 minutes. If oral use is required, Furosemid is preferred (onset of action – 30 min).   
 If there’s a significant AP rise, solutions of antihypertensive drugs are administered parenterally, often – i/v (clonidine, Sodium nitroprusside, nitroglycerine,  hydralazine, Bendazol, Riodipin, Enalaprilat, Azamethonium, Furosemid).